The present invention relates to certain compounds of the formula (II.sup.A) depicted below, which are useful in the synthesis of certain .beta.-adrenergic receptor agonists having the general formula (I): ##STR3##
where R.sup.1 and R.sup.2 are as defined herein for the compound of formula (II.sup.A) hereinbelow and Y.sup.1, Y.sup.2 and Y.sup.3 are chemical substituents which can be attached to the atoms to which they are attached. These substituents confer .beta.-adrenergic receptor activity and as such the compounds of formula (I) have utility as hypoglycemic and antiobesity agents. Examples of such substituents and the resultant .beta.-adrenergic receptor agonists can be found in PCT Publication No. WO 94/29290 published Dec. 22, 1994. The invention also relates to a process for synthesizing the compounds of formula (II) hereinbelow and to a process for synthesizing compounds of the formula (III), which are useful in the synthesis of the compounds of formula (I). The invention further relates to processes for synthesizing compounds of formula (I). The .beta.-adrenergic receptor agonists also possess utility for increasing lean meat deposition and/or improving the lean meat to fat ratio in edible animals.
The .beta.-adrenergic receptor agonists further possess utility in the treatment of intestinal motility disorders, depression, prostate disease, dyslipidemia, and airway inflammatory disorders such as asthma and obstructive lung disease.
The disease diabetes mellitus is characterized by metabolic defects in production and/or utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates carbohydrate utilization. Type II diabetes, or non-insulin dependent diabetes, often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese.
The .beta.-adrenergic receptor agonists effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
The .beta.-adrenergic receptor agonists also reduce body weight or decrease weight gain when administered to mammals. The ability of .beta.-adrenergic receptor agonists to affect weight gain is due to activation of .beta.-adrenergic receptors which stimulate the metabolism of adipose tissue.
.beta.-Adrenergic receptors have been categorized into .beta..sub.1 -, .beta..sub.2 - and .beta..sub.3 -subtypes. Agonists of .beta.-receptors promote the activation of adenyl cyclase. Activation of .beta..sub.1 -receptors invokes increases in heart rate while activation of .beta..sub.2 -receptors induces relaxation of skeletal muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors. Activation of .beta..sub.3 -receptors is known to stimulate lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids) and metabolic rate (energy expenditure), and thereby promote the loss of fat mass. Compounds that stimulate .beta.-receptors are, therefore, useful as anti-obesity agents, and can also be used to increase the content of lean meat in edible animals. In addition, compounds which are .beta..sub.3 -receptor agonists have hypoglycemic or anti-diabetic activity, but the mechanism of this effect is unknown.
Until recently .beta..sub.3 -adrenergic receptors were thought to be found predominantly in adipose tissue. .beta..sub.3 -receptors are now known to be located in such diverse tissues as the intestine (J. Clin. Invest., 91, 344 (1993)) and the brain (Eur. J. Pharm., 219,193 (1992)). Stimulation of the .beta..sub.3 -receptor has been demonstrated to cause relaxation of smooth muscle in colon, trachea and bronchi. Life Sciences, 44(19), 1411 (1989); Br. J. Pharm., 112, 55 (1994); Br. J. Pharmacol., 110, 1311 (1993). For example, stimulation of .beta..sub.3 -receptors has been found to induce relaxation of histamine-contracted guinea pig ileum, J.Pharm.Exp.Ther., 260, 1, 192 (1992).
The .beta..sub.3 -receptor is also expressed in human prostate. Because stimulation of the .beta..sub.3 -receptor causes relaxation of smooth muscles that have been shown to express the .beta..sub.3 -receptor (e.g. intestine), one skilled in the art would predict relaxation of prostate smooth muscle. Therefore, .beta..sub.3 -agonists will be useful for the treatment or prevention of prostate disease.
Examples of .beta.-adrenergic receptor agonists which can be synthesized using the compounds of formula (III) can be found in PCT Publication No. WO 94/29290 published Dec. 22, 1994, U.S. patent application Ser. No. 08/312,027 filed Sep. 26, 1994, PCT Application No. PCT/IB95/00344 filed May 10, 1995 and U.S. Provisional Application No. 60/015,216 filed Apr. 9, 1996, all of which are assigned to the assignee hereof.
With regard to the process of synthesizing a compound of formula (II) wherein X is OH, defined hereinbelow, of the present invention, the chemical literature teaches that addition of osmium tetroxide to olefins, including the olefin moiety of allylic and styryl compounds, results in the addition of two OH groups to the double bond, with one OH group being added to each carbon atom constituting the double bond. (see Advanced Organic Chemistry, March, John Wiley and Sons, NY, N.Y., 1985, 3rd Ed.) Two OH groups can also be added to double bonds by reacting the compound containing the double bond with (i) hydrogen peroxide and catalytic amounts of osmium tetroxide, (ii) alkaline potassium permanganate; (iii) hydrogen peroxide and formic acid; or (iv) iodine and silver benzoate. These methods all suffer from the drawback that they do not react stereospecifically with a prochiral carbon atom of the double bond to create an optically active dihydroxy compound.
U.S. Pat. No. 5,019,578 discloses a process for preparing epoxy-pyridine compounds. That process involves hydroxy bromination of a 5-ethenyl pyridine derivative followed by cyclization to the epoxide and suffers from the disadvantage that the bromohydrin is prepared as a racemic mixture.